TY - JOUR
T1 - COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy
AU - ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)
AU - Weckmann, Markus
AU - Bahmer, Thomas
AU - Bülow Sand, Jannie Marie
AU - Rank Rønnow, Sarah
AU - Pech, Martin
AU - Vermeulen, Cornelis
AU - Faiz, Alen
AU - Leeming, Diana Julie
AU - Karsdal, Morten Asser
AU - Lunding, Lars
AU - Oliver, Brian George G
AU - Wegmann, Michael
AU - Ulrich-Merzenich, Gudrun
AU - Juergens, Uwe R
AU - Duhn, Jannis
AU - Laumonnier, Yves
AU - Danov, Olga
AU - Sewald, Katherina
AU - Zissler, Ulrich
AU - Jonker, Marnix
AU - König, Inke
AU - Hansen, Gesine
AU - von Mutius, Erika
AU - Fuchs, Oliver
AU - Dittrich, Anna-Maria
AU - Schaub, Bianca
AU - Happle, Christine
AU - Rabe, Klaus F
AU - van de Berge, Maarten
AU - Burgess, Janette Kay
AU - Kopp, Matthias Volkmar
N1 - Copyright ©The authors 2021. For reproduction rights and permissions contact [email protected].
PY - 2021/12/1
Y1 - 2021/12/1
N2 - BACKGROUND: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test.RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5).CONCLUSION: C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.
AB - BACKGROUND: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test.RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5).CONCLUSION: C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.
U2 - 10.1183/13993003.03969-2020
DO - 10.1183/13993003.03969-2020
M3 - Article
C2 - 34326188
SN - 0903-1936
VL - 58
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 6
M1 - 2003969
ER -